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The addition of the 7-valent pneumococcal conjugate vaccine (PCV7) to the routine immunization schedule in the United States for infants has produced a much more favorable impact on the incidence of acute otitis media (AOM) than anticipated. Because the serotypes included in PCV7 were those most frequently expressing antibiotic resistance in 2001, predictions were made that up to 98% of pneumococcal AOM episodes would be caused by penicillin susceptible strains. However, recent studies have shown that the benefits of PCV7 are becoming eroded. Replacement serotypes of pneumococci have emerged, expressing polysaccharide capsules different from those included in PCV7, with increasing frequency. These replacement strains are coming to dominate in the nasopharynx and in AOM isolates (and in invasive disease). Expansion in the isolation of serotypes 3, 7F, 15B/C/F, 19A, 22F, 33F, and 38 has been described in various surveillance systems. Pneumococcal strains expressing non-PCV7 capsular serotypes also appear to be rapidly acquiring resistance to penicillin and other antibiotics. Emergence of strains of pneumococci expressing non-PCV7 capsular serotypes is occurring by multiple mechanisms including capsular switching as suggested by molecular epidemiology studies. Expansion of the number of serotypes included in pneumococcal conjugate vaccines is needed to sustain a long-term benefit from immunization against these bacteria.